ASH Annual Meeting: New Tools and Therapies for Improving ...

ASH Highlights/Winter 2018

ASH Annual Meeting: New Tools and Therapies

for Improving Lymphoma Patient Outcomes

C

apping off a year that witnessed the

treatment landscape in lymphoma expand considerably due to several

approvals from the U.S. Food and Drug

Administration (FDA), the 2017 Annual

Meeting of the American Society for

Hematology (ASH) lived up to its reputation as a showcase for the significant

strides researchers are making in improving patient outcomes for blood cancers

and other hematologic malignancies.

Highlights of the 2017 Annual Meeting,

held December 9-12 in Atlanta, Georgia,

included clinical trials testing promising

new therapies, follow-up studies showing

sustainable results of the first generation of immunotherapies, new tools for

assessing patient prognosis and improved

methods for understanding how potential

new therapies will translate from the lab

to the clinic.

The ASH Annual Meeting has for nearly

60 years been the leading conference for

hematologists, oncologists, and researchers across the hematologic malignancies,

offering a crucial forum for international

discussion of new research and its implications for patient care. More than 20,000

2017 Annual Meeting Highlights

Acalabrutinib

pg. 2

clinical results in MCL and CLL

Basic and Translational Science

pg. 3

circulating tumor DNA and new disease models in the lab

Venetoclax and CLL

pg. 4

new clinical trial and translational data

Targeted Therapies in the Pipeline

pg. 5

early clinical results for new therapies in B- and T-cell NHL

Immunotherapies

pg. 6

follow-up results for CAR-T, new checkpoint inhibitors

Epidemiology and Clinical Endpoints

pg. 9

the impact of physical activity on patient outcomes

researchers attend the Annual Meeting

each year. The Lymphoma Research

Foundation (LRF) was well represented

at the meeting in presentations and contributions from its grantees, Scientific

Advisory Board (SAB) members, and members of its research colloquium and pro-

fessional education steering committees.

Over 480 lymphoma-related abstracts

presented at the 2017 Annual Meeting

included at least one LRF researcher as

an author, with 114 of those researchers

serving as the abstract¡¯s presenter -- a role

FEATURED IN THIS ISSUE: Adherence in Oral Therapies Workshop

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Page 8

LRF¡¯s October 2017 scientific workshop, ¡°Adherence and Oral Therapies in Lymphoma and CLL¡± produced

several recommendations for researching and managing issues around oral therapy regimens.



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LETTER FROM THE CEO

Dear LRF Friends and Supporters,

This past December, I had the opportunity to attend the 59th Annual Meeting of the

American Society of Hematology (ASH) in Atlanta, Georgia. One of the world¡¯s premier

events in hematology, this meeting offers an opportunity for experts in the field to review thousands of scientific abstracts and research papers highlighting critical updates in the study and

treatment of lymphoma. This edition of Research Report features a selection of the interesting

studies discussed at ASH, many of which featured contributions from Foundation grantees,

Scientific Advisory Board members, and scientific leadership.

We often focus on clinical trial results emerging from ASH, but this year¡¯s meeting included significant advances in

translational and laboratory-based research, especially involving new tools for predicting patient prognosis and testing new

therapies more accurately in the lab. We are proud that LRF-funded research figured in several of these key developments,

which are explored in more detail on page two.

In October 2017, LRF hosted a scientific workshop on adherence in oral therapies in lymphoma and CLL. As oral

therapies become a standard therapy for many lymphomas, management of this therapy becomes an increasingly critical

issue for many clinicians. Please see page eight for a summary of the recommendations from the workshop, which will be

released as a white paper in the coming weeks.

This special edition of Research Report allows us to highlight the results of your support for lymphoma research. Thank you

for all you do in helping the Foundation advance innovative research and impact the lives of those we exist to serve.

Sincerely,

Meghan Gutierrez

Chief Executive Officer

ASH 2017

[CONTINUED FROM PAGE 1]

generally reserved for a project¡¯s lead or senior researcher. The

45 member LRF Scientific Advisory Board (SAB), a peer-elected

group of expert clinicians and scientists in lymphoma who help

guide LRF¡¯s research portfolio, saw 93 percent of its members

contribute to an abstract, with 58 percent serving as presenters.

Meanwhile, 61 percent of LRF grantees who were awarded a

grant in the past decade were included on an ASH abstract, with

15 abstracts directly related to LRF-funded research.

¡°It is always encouraging to see the large number of LRF

Scientific Advisory Board members and LRF grantees that

participate in the ASH Annual Meeting,¡± said Thomas M.

Habermann, MD of Mayo Clinic, Chair of the LRF Scientific

Advisory Board. ¡°This year, to see so many of this group asso-

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Research Report

ciated with key findings in both clinical and laboratory research

speaks to the caliber of scientists that are both steering and

contributing to LRF¡¯s investment in cutting-edge lymphoma

research.¡±

Highlights of the Annual Meeting¡¯s clinical research and other

studies related to new therapies continue below. Advances in

prognostic and laboratory research tools may be found on pg.

2. An overview of epidemiology and clinical endpoints research

begins on pg. 10.

New Therapies: Acalabrutinib

An early U.S. Food and Drug Administration (FDA) approval

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ASH 2017

Foundation Grantees Contribute Key Developments in New Tools

for Lymphoma Research and Patient Care

T

he 2017 ASH Annual Meeting¡¯s lymphoma research was

also a strong meeting for basic and translational science

research (research taking place in a laboratory setting and/

or involving the transfer of laboratory research to the clinic).

Several abstracts presented signficant improvements on existing tools for studying lymphoma development in the body,

which will help researchers improve both their assessment

of existing therapies and their exploration of new ones. As

with the clinical developments, LRF grantees and SAB members contributed to many of these developments, including

through their LRF-funded research.

An area of significant interest at the 2017 Annual Meeting was

circulating tumor DNA (ctDNA), and its potential applications

in predicting patient outcomes. When predicting patient

outcomes, tumor burden, or the relative mass of the disease

present in the body, is a reliable factor for identifying high-risk

patients who may need more aggressive treatment. However,

current tools for measuring tumor burden are not as precise as

researchers would like or require the patient to undergo additional imaging tests. ctDNA consists of DNA from dying tumor

cells that is released directly into the bloodstream; because it

can be monitored through a high throughput sequencing of a

patient¡¯s blood sample, it is a less invasive and, in some cases,

less stressful way of measuring a patient¡¯s prognosis.

LRF grantees Ash Alizadeh, MD (also an SAB member) and

David Kurtz, MD, both of Stanford University have taken a

key role in investigating this topic ¨C Dr. Kurtz¡¯ project for the

Lymphoma Clinical Research Mentoring Program (LCRMP)

workshop in 2015 was part of the results presented at the

Annual Meeting, and Dr. Alizadeh¡¯s Follicular Lymphoma

Pathways Grant project was a precursor to the concept of circulating tumor DNA as a prognostic test. At the Annual Meeting,

their studies on this topic made up several abstracts, including

two presentations delivered by Dr. Kurtz.

The most significant of their presentations was a validation

study of ctDNA in diffuse large B-cell lymphoma (DLBCL) ¨C 183

patients from six centers around the world had their blood

screened for ctDNA prior to receiving treatment, with 97

percent of patients having detectable ctDNA in their blood.

Moreover, Dr. Kurtz and his collaborators found a consistent

David Kurtz, MD of Stanford University, presents a poster on his

LRF-funded project on circulating tumor DNA at the 2017 North

American Educational Forum on Lymphoma.

correlation between the amount of ctDNA detected and the

patient¡¯s International Prognostic Index (IPI) risk group, a standardized method for measuring a patient¡¯s prognosis and likelihood of relapse or refractory disease. A similar correlation was

found between the amount of ctDNA detected and the amount

of time before a patient¡¯s disease progressed after treatment,

with higher ctDNA levels correlating with less time before progression. The researchers noted this study verified ctDNA¡¯s use

as a prognostic tool and could be used to make more accurate

estimates of a patient¡¯s disease burden and refine their treatment appropriately.

?Contributors to this study also included MCL Consortium Member Mark

Roschewski, MD of National Heart, Lung and Blood Institute, LRF Scholar

Jason Westin, MD of MD Anderson Cancer Center, and former SAB member

Wyndham Wilson, MD of the National Cancer Institute.

In a session subtitled ¡°New Tools and Emerging

Immunomodulatory Approaches for Non-Hodgkin Lymphomas¡±

several abstracts from LRF affiliated researchers examined new

methods by which researchers can assess new therapies¡¯ potential in the laboratory before their first in-human tests. Several of

the abstracts presented demonstrated construction of patient

derived tumor xenograft (PDTX) models in various subtypes.

[CONTINUED ON PAGE 10]



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ASH 2017

ASH 2017

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for acalabrutinib (Calquence) in mantle

cell lymphoma (MCL) shortly before

the Annual Meeting made data on this

promising new novel agent a topic of

great interest. Acalabrutinib works by

inhibiting the Bruton¡¯s tyrosine kinase

(BTK) pathway, a key genetic pathway to

the growth of lymphoma cells. Data from

the ACE-LY-004 trial, cited by the FDA as

being key to their approval, were presented by lead investigator Michael Wang,

MD, of the MD Anderson Cancer Center.

Dr. Wang, who is a member of LRF¡¯s MCL

Consortium, presented data from 124

patients with relapsed/refractory MCL,

who took acalabrutinib orally twice daily,

until their disease progressed. At a median follow-up of 15.2 months, over half of

the patients (56 percent) still remained

on the study, with 81 percent of patients

exhibiting some response to the therapy.

Because of the number of patients still

active in the study, a median progression

free survival rate and overall survival

rate had not yet been reached. Adverse

effects of the drug were limited, with only

6 percent of patients discontinuing due

to their effects. More significantly, there

were no reports of atrial fibrillation (irregular heartbeat), which may indicate an

improvement over existing BTK-inhibitors

such as ibrutinib, and offer an alternative

therapy for patients particularly at risk for

that adverse effect.

?Additional contributors to this study included MCL Consortium members Andre Goy, MD

of John Theurer Cancer Center (also a former

SAB member), Simon Rule, MD of Plymouth

University (UK), and Bijal Shah, MD, of Moffitt

Cancer Center.

As with other BTK inhibitors, acalabrutinib is being tested in a variety of B-cell

non-Hodgkin lymphomas (NHL), with

data from the ACE-CL-003 study showing

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Research Report

significant effects for chronic lymphocytic leukemia (CLL) patients. The study,

which is in an earlier phase than the

MCL study, has treated 19 patients who

were receiving their first therapy and

26 relapsed/refractory patients with a

combination of oral acalabrutinib and

intravenous obinutuzumab. As with the

MCL study, most patients (41 of 45, or 91

percent) were still being treated when

data was submitted, with 94 percent of

relapsed patients and 86 percent of the

patients receiving their first therapy having a duration of response of at least 18

months, and only one patient reporting

atrial fibrillation, who did not need to discontinue treatment. The investigators on

this trial noted that their results indicate

this may be an effective new combination for both first line and relapsed CLL

patients.

?Contributors to this study include LRF grantee

Farrukh Awan, MD and former SAB member

John Byrd, MD, both of The Ohio State University

Comprehensive Cancer Center.

New Combination Therapies:

Venetoclax and CLL

Promising news for CLL patients also

included results from two trials combining existing therapies with venetoclax

(Venclexta), an oral therapy which works

by inhibiting the pathway BCL-2. In 2016,

venetoclax was approved for CLL patients

with 17p deletion who have received at

least one prior therapy. Data from the

TAP CLARITY trial in the United Kingdom,

which administered a combination of

venetoclax and ibrutinib for relapsed/

refractory CLL patients with and without

17p deletion, reported that all of the 38

evaluable patients on the study experienced at least a partial response ¨C an

objective response rate of 100 percent.

Furthermore, 32 percent of these patients

had no disease following treatment, even

when testing for minimal residual disease

(MRD) in bone marrow, one of the most

sensitive measurements for detecting

trace amounts of cancerous cells. Only

one patient on the trial experienced

tumor lysis syndrome (TLS), a severe

adverse effect that has been a concern in

some single agent venetoclax trials. This

patient was able to pause treatment until

the TLS cleared and then resume with no

further TLS. Peter Hillmen, MBChB, FRCP,

FRCPath, PhD, of the University of Leeds

and St. James¡¯s Institute of Oncology in

the UK, presented the trial at ASH, and

noted in a release that the response rate,

number of patients with no minimal

residual disease, and lack of increase in

toxicity are all encouraging signs of an

effective treatment for a population that

has not responded to other therapies.

Similar success was reported in a trial of

venetoclax and rituximab (Rituxan) in

patients with relapsed/refractory CLL.

The MURANO trial, a large-scale international trial including contributions

from Peter Hillmen, lead investigator on

the TAP-CLARITY trial, and former LRF

SAB member Thomas J. Kipps, MD of

the University of California, San Diego,

enrolled 389 patients who had received

between one and three prior therapies,

and randomized them into two arms.

Patients received either rituximab plus

bendamustine (a current standard

approach for relapsed CLL), or rituximab

plus venetoclax. The researchers reported two-year progression free survival

rates of 84.9 percent for the 194 patients

in the venetoclax arm, vs 36.3 percent

in the bendamustine arm, a benefit that

extended across both high- and low- risk

patients. The researchers further reported

an overall response rate of 93.3 percent

with venetoclax versus 67.7 percent with

bendamustine, indicating that the venetoclax combination was not only effec[CONTINUED NEXT PAGE]

ASH 2017

tive for more patients, but prompted

a longer response before any disease

progression. The MURANO results will

be submitted to the FDA in support of

converting both the venetoclax/rituximab combination, which received a

breakthrough therapy designation in

2016, and the single-agent venetoclax¡¯s

accelerated approval into full approval.

Because CLL patients often develop

resistance to therapy over time, the

promising clinical trial results for venetoclax were accompanied by questions

of how to counteract this effect. The

results of a laboratory study from the

lab of Catherine J. Wu, MD of DanaFarber Cancer Institute, a prior recipient

of an LRF CLL grant, provided early data

on a potential resistance-countering

strategy. Dr. Wu and her collaborators

looked at altered RNA-splicing, a common mutation in CLL cells, and assessed

whether combining venetoclax with

a splicing modulator, E7107 (or E7),

designed to change the RNA-alterations

into targets that can be more receptive to venetoclax. In both in vitro and

mouse model tests, treatment with E7

and venetoclax resulted in increased

effectiveness for the therapy compared

to either agent alone, including in a

mouse model that appeared initially

resistant to venetoclax. The researchers

noted that these results indicate that

splicing modulators deserve further

exploration as a potential strategy to

overcome drug resistance and widen

the number of patients for whom venetoclax is effective.

?Other contributors to this study included

LRF grantees Thomas Kipps, MD of University

New Targeted Therapies: In the

Pipeline

Promising results for new targeted therapies in B-cell NHL were also presented

during the 2017 ASH Annual Meeting. A

trial spearheaded by two LRF SAB members, Brad S. Kahl, MD of Washington

University School of Medicine in Saint

Louis ¨C who presented the results ¨C and

Owen A. O¡¯Connor, MD of Columbia

University Medical Center, reported the

first in-human data for loncastuximab

tesirine, an antibody drug conjugate,

in relapsed/refractory B-cell NHL, primarily diffuse large B-cell lymphoma

(DLBCL). Antibody drug conjugates are

a class of therapy combining a monoclonal antibody (a type of cell found

in the immune system that is able to

target specific abnormalities) and a

drug designed to kill cancerous cells.

Loncastuximab tesirine specifically

targets CD19, a biomarker that is often

present in B-cell lymphomas. The study

recruited relapsed/refractory B-cell NHL

patients with aggressive disease who

did not respond to other therapies or

had no other treatment options. The

68 patients who were evaluable at the

time of presentation reported an overall response rate of 60.3 percent, with

35.3 percent experience a complete

response. Dr. Kahl noted that nearly all

patients experienced some degree of

adverse effects, which could be very

persistent but which were generally

not severe; eight patients (10 percent) discontinued treatment due to

side effects. Due to the encouraging

number of responses, however, future

studies are planned in specific NHL subtypes, including DLBCL.

of California San Diego (also a former SAB

member) and Lili Wang, MD, PhD of Beckman

Research Institute, City of Hope, as well as

Matthew S. Davids, MD, PhD, of Dana-Farber

Cancer Institute, a Lymphoma Rounds

Steering Committee member.

For patients with cutaneous T-cell

lymphoma (CTCL), findings from the

MAVORIC study offered new hope for a

therapy with a longer lasting response.

The randomized trial tested mogam-

ulizumab (Poteligeo), an antibody

therapy targeting the receptor protein

CCR4, against the standard CTCL therapy vorinostat, for patients with either

mycosis fungoides or S¨¦zary syndrome

subtypes of CTCL who had failed to

respond to at least one prior therapy.

Patients in the mogamulizumab arm

had a median progression free survival

of 6.7 months, compared to 3.8 months

in the vorinostat arm ¨C significantly 28

percent of patients responded in some

degree to mogamulizumab compared

to only 4.8 percent with vorinostat.

Because of the disparity in results,

patients in the vorinostat arm whose

disease progressed or who had severe,

intolerable side effects were allowed

to cross over to the mogamulizumab

arm; 30.1 percent of that group had a

response to the new treatment. Based

on the results of this trial, the U.S. FDA

granted a priority review to mogamulizumab for relapsed/refractory CTCL

patients; a decision is expected in mid2018.

?Contributions to this study included LRF

SAB member and grantee Steven M. Horwitz,

MD of Memorial Sloan Kettering Cancer, and

Lauren Pinter-Brown, MD of University of

California, Irvine, Center, a Lymphoma Rounds

Steering Committee member.

An international trial of a new Bruton¡¯s

tyrosine kinase (BTK) inhibitor, zanubrutinib (also known as BGB-3111), also

demonstrated promising clinical activity for a variety of NHL, including significant results in marginal zone lymphoma (MZL). The trial, which was intended

to test varying dose levels for safety and

efficacy, enrolled 99 patients with NHL

subtypes including both aggressive

MCL and DLBCL (65 patients) and indolent follicular lymphoma (FL) and MZL

(34 patients). In the indolent group, 17

evaluable FL patients had an 18 percent

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